Endometrial cancer (EC) is the most common gynecologic malignancy in the United States and is believed in most cases to be related to overexposure to unopposed estrogens. EC is usually curable with surgery. Alternatively, progesterone, a natural inhibitor of cellular proliferation of the endometrium, has been used with limited success for endometrial hyperplasia or EC in patients who are concerned about fertility. The mechanisms of progesterone action, however, have yet to be defined. Progesterone can influence regulatory components of the cell cycle (e.g. cyclins, cyclin dependent kinases; cdks). Our recent studies have demonstrated that Cables, a novel cell cycle regulatory protein, is lost at a high frequency in EC. Cables appears to act as a linker protein, which facilitates tyrosine 15 phosphorytation of some cdks by non-receptor tyrosine kinases. Cdk2 regulates the G1 S-phase transition of the cell cycle and cdk2 tyrosine phosphorylation is inhibitory and leads to decreased cdk2 activity and slows cell growth. Cables enhances this inhibitory phosphorylation, so loss of Cables should result in increased, and possibly uncontrolled, cell growth. Progesterone appears to transcriptionally regulate Cables in epithelial cells derived from proliferating endometrium, but not in EC cell lines. More interesting, the Cables deficient mice have evidence of endometrial hyperplasia at 3 months of age and as such appears to be a mouse model that mimics the human disease. Collectively, these data have led us to hypothesize that Cables expression in normal endometrial epithelium is hormonally regulated, and Cables is absent or tess effective in transformed/transforming cells. Furthermore, we believe that a loss, or a reduced level of, Cables leads to atypical endometrial hyperptasia and/or neoplasia. To test our hypotheses, we have proposed the following aims 1) Determine the role of progesterone in mediating Cables induced inhibition of endometrial cell proliferation in vitro, 2) Determine if Cables is required for the anti-proliferative effects of progesterone in endometrial cells, and if loss of Cables facilitates EC development in vivo, 3) Investigate the endometrial changes associated with proliferation and differentiation during the estrous cycle and abnormal endometrial growth in Cables deficient mice, 4) Determine the mechanism of Cables gene inactivation in primary :human EC. The studies in this proposal will help determine the: role of Cables in I normal and malignant endometrial epithelium.